A new method for induced fit docking (GENIUS) and its application to virtual screening of novel HCV NS3-4A protease inhibitors

作者：Takaya Daisuke; Yamashita Atsuya; Kamijo Kazue; Gomi Junko; Ito Masahiko; Maekawa Shinya; Enomoto Nobuyuki; Sakamoto Naoya; Watanabe Yoshiaki; Arai Ryoichi; Umeyama Hideaki; Honma Teruki; Matsumoto Takehisa; Yokoyama Shigeyuki^*

来源：Bioorganic & Medicinal Chemistry, 2011, 19(22): 6892-6905.

DOI：10.1016/j.bmc.2011.09.023

• HCV
• NS 3-4A protease
• Structure based drug design
• Ligand docking
• Virtual screening

Hepatitis C virus (HCV) is an etiologic agent of chronic liver disease, and approximately 170 million people worldwide are infected with the virus. HCV NS3-4A serine protease is essential for the replication of this virus, and thus has been investigated as an attractive target for anti-HCV drugs. In this study, we developed our new induced-fit docking program (GENIUS), and applied it to the discovery of a new class of NS3-4A protease inhibitors (IC(50) = 1-10 mu M including high selectivity index). The new inhibitors thus identified were modified, based on the docking models, and revealed preliminary structure-activity relationships. Moreover, the GENIUS in silico screening performance was validated by using an enrichment factor. We believe our designed scaffold could contribute to the improvement of HCV chemotherapy.

• 出版日期2011-11-15